The study investigated the effect of ethanol extract of Zapoteca portoricensis roots on malaria-infected mice. The effect of ethanol extract on malaria infected mice was studied by assaying percentage parasitaemia, some liver marker enzymes and kidney function markers. The acute toxicity study showed that the ethanol extract had LD 50 above 2900 mg kgG 1 b.wt. Malaria infected mice treated with the ethanol extract had significant (p<0.05) decrease in the mean percentage parasitaemia when compared with group 2 mice (malaria untreated). The AST activity showed significant (p<0.05) increase in all the test groups when compared to normal control on day 14 but significantly (p<0.05) reduced in all the treated groups when compared to group 2 mice on day 28. The ALT and ALP activities decreased significantly (p<0.05) in all the test groups when compared to group 2 mice. The urea concentration significantly (p<0.05) decreased in the normal control, group 4 and 5 when compared with group 2 mice. Creatinine concentration decreased significantly (p<0.05) in the normal control, group 3 and group 4 when compared to group 2 mice on day 14, however, on day 28, no significant (p>0.05) differences were observed in the creatinine concentrations in all the groups when compared to normal control. The results suggest that the ethanol extract of Zapoteca portoricensis roots is relative safe has no negative effects on liver and kidney with huge potentials in the management of malaria.